The Baculoviridae are a family of enveloped animal viruses that are pathogenic to invertebrates, primarily insects. Baculoviruses have large circular double-stranded DNA genomes ranging from approximately 80 to 180 kbp. Baculoviruses are characterized by an infection cycle that produces two virion phenotypes that are structurally and functionally distinct. Blissard, G. W. and Rohrmann, G. F., Annu. Rev. Entomol. 35: 127-155 (1990). The first virion phenotype produced in the infection cycle is the budded virus (BV). Production of the BV begins when viral nucleocapsids bud through the plasma membrane into the extracellular space. BV is responsible for the systemic infection of insect cells and tissues in vivo and is highly infectious in cell culture systems. The second virion phenotype, the occlusion-derived virus (ODV), is produced in the very late phase of the infection cycle when nucleocapsids become enveloped within the nucleus. Although BV and ODV appear to be identical in nucleocapsid structure, they differ in the sources of their envelopes. This difference results in differences in biochemical compositions and correlates with observed differences in relative infectivities for different tissues within the insect and in tissue culture. Keddie, B. A. and Volkman, L. E., J. Gen Virol. 66:1195-1200 (1985).
Infectivity of BV is dependent on the major BV-specific envelope glycoprotein, gp67. See, e.g., Oomens et al., Virology 209:592-603 (1995). This envelope protein is an extensively processed type I integral membrane glycoprotein that has been studied in some detail. See, e.g., Jarvis, D. L. and Garcia, A., Virology 205:300-313 (1994); Blissard, G. W. and Wenz, J. R., J. Virol. 66:6829-6835 (1992).
The gp67 proteins from three baculoviruses, Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus (OpMNPV), Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV), and Choristoneura fumiferana multicapsid nuclear polyhedrosis virus (CfMNPV), show a high degree of amino acid sequence similarity (Blissard, G. W. and Rohrmann, G. F., Virology 170:537-555 (1989); Hill, J. E. and Faulkner, P., J. Gen. Virol. 75:1811-1813 (1994)) with the predicted extracellular domains showing at least 82% identity across all three baculovirus gp67 proteins. The gp67 genes of AcMNPV and OpMNPV have been mapped, cloned, and sequenced (Whitford et al., J. Virol.63:1393-1399 (1989); Blissard, G. W. and Rohrmann, G. F., Virology 170:537-555 (1989)).
The important role of gp67 in BV infectivity has been demonstrated by the neutralization of BV infectivity with monoclonal antibodies specific to gp67. See, Hohmann, A. W and Faulkner, P., Virology 125:432-444 (1983); Volkman et al., Virology 133:354-362 (1984). Later studies demonstrated that gp67 is necessary and sufficient for low pH-activated membrane fusion activity, consistent with the role of gp67 in viral entry through the low pH environment of the endosome. Blissard, G. W. and Wenz, J. R., J. Virol. 66:6829-6835 (1992). More recently, Monsma et al., J. Virol. 70:4607-4616 (July 1996), used a stably transfected insect cell line that constitutively expressed the gp67 of Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus (OpMNPV), to generate a recombinant gp67-null Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV) baculovirus. They then examined the effect of the gp67-null mutation on viral transmission in both cell culture and insect larvae. Monsma et al., demonstrated that gp67 is an essential virion structural protein that is required for propagation of the budded virus from cell to cell and for systemic infection of the host insect.
Despite the fact that gp67 is a well studied baculovirus envelope glycoprotein with a documented role in cell to cell transmission of infection, the recognition that gp67 induces Type I and Type II interferon production (and thereby confers, inter alia, anti-viral activity) has previously gone unnoticed.
Interferons (IFNs) are a well known family of cytokines secreted by a large variety of eukaryotic cells upon exposure to various mitogens. The interferons have been classified by their chemical and biological characteristics into three groups: IFN-alpha (leukocytes), IFN-beta (fibroblasts), and IFN-gamma (lymphocytes). IFN-alpha and beta are known as Type I interferons; IFN-gamma is known as Type II or immune interferon. The IFNs exhibit anti-viral, immunoregulatory, and antiproliferative activity. The clinical potential of interferons has been recognized, and will be summarized below:
Anti-viral: IFNs have been used clinically for anti-viral therapy, for example, in the treatment of AIDS (Lane, H. C., Semin. Oncol. 18:46-52 (October 1991)), viral hepatitis including chronic hepatitis B and hepatitis C (Woo, M. H. and Burnakis, T. G., Ann. Pharmacother. 31:330-337 (March 1997); Gibas, A. L., Gastroenterologist 1:129-142 (June 1993)), papilloma viruses (Levine, L. A. et al., Urology 47:553-557 (April 1996)), herpes (Ho, M., Annu. Rev. Med. 38:51-59 (1987)), cytomegalovirus (CMV) (Yamamoto, N. et al., Arch. Virol. 94:323-329 (1987)), viral encephalitis (Wintergerst et al., Infection 20:207-212 (July 1992)), and in the prophylaxis of rhinitis (Ho, M., Annu. Rev. Med. 38:51-59 (1987)).
Anti-parasitic: IFNs have been suggested for anti-parasite therapy, for example, IFN-gamma for treating Cryptosporidium parvum infection (Rehg, J. E., J. Infect. Des. 174:229-232 (July 1996)).
Anti-bacterial: IFNs have been used clinically for anti-bacterial therapy. For example, IFN-gamma has been used in the treatment of multidrug-resistant pulmonary tuberculosis (Condos et al., Lancet 349:1513-1515 (1997)).
Anti-cancer: Interferon therapy has been used in the treatment of numerous cancers (e.g., hairy cell leukemia (Hofmann et al., Cancer Treat. Rev. 12 (Suppl. B):33-37 (December 1985)), acute myeloid leukemia (Stone. et al., Am. J. Clin. Oncol. 16:159-163 (April 1993)), osteosarcoma (Strander et al., Acta Oncol. 34:877-880 (1995)), basal cell carcinoma (Dogan et al., Cancer Lett. 91:215-219 (May 1995)), glioma (Fetell et al., Cancer 65:78-83 (January 1990)), renal cell carcinoma (Aso et al., Prog. Clin. Biol. Res. 303:653-659 (1989)), multiple myeloma (Peest et al., Br. J. Haematol. 94:425-432 (September 1996)), melanoma (Ikic et al., Int. J. Dermatol. 34:872-874 (December 1995)), and Hodgkin's disease (Rybak et al., J. Biol. Response Mod. 9:1-4 (February 1990)). Synergistic treatment of advanced cancer with a combination of alpha interferon and temozolomide has also been reported (Patent publication WO 9712630 to Dugan, M. H).
Immunotherapy: IFNs have been used clinically for immunotherapy or more particularly, immunosuppression, for example, to prevent graft vs. host rejection, or to curtail the progression of autoimmune diseases, such as arthritis, multiple sclerosis, or diabetes. IFN-beta is approved for sale in the United States for the treatment of multiple sclerosis (i.e., as an immunosuppressant). Recently, it has been reported that patients with multiple sclerosis have diminished production of type I interferons and interleukin-2 (Wandinger et al., J. Neurol. Sci. 149:87-93 (1997)). In addition, immunotherapy with recombinant IFN-alpha (in combination with recombinant human IL-2) has been used successfully in lymphoma patients following autologous bone marrow or blood stem cell transplantation, and may intensify remission following transplantation (Nagler et al., Blood 89:3951-3959 (June 1997)).
Anti-allergy: The administration of IFN-gamma has been used in the treatment of allergies in mammals (See, Patent Publication WO 8701288 to Parkin, J. M. and Pinching, A. J.). It has also recently been demonstrated that there is a reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma (van der Pouw Kraan et al., J. Immunol. 158:5560-5565 (1997)). Thus, IFN may be useful in the treatment of allergy by inhibiting the humoral response.
Vaccine adjuvantation: Interferons may be used as an adjuvant or co-adjuvant to enhance or stimulate the immune response in cases of prophylactic or therapeutic vaccination (Heath, A. W. and Playfair, J. H. L., Vaccine 10:427-434 (1992)).
Clearly, there exists a need in the art for the discovery of proteins that stimulate endogenous, multi-form interferon production for numerous applications, in e.g., immunotherapy, as well as anti-viral, anti-parasitic, anti-bacterial, or anti-cancer therapies, or any medical condition or situation where an increased production of interferon is desired.